What is the unfolded protein response (UPR)?

Secretory and membrane proteins, such as hormones and receptors that regulate intricate physiological processes, are exclusively synthesized at the endoplasmic reticulum (ER). The accumulation of unfolded proteins due to insufficient folding capacity in ER is referred to as ER stress The unfolded protein response (UPR) is an adaptive mechanism that helps cells cope with ER stress by attenuating protein translation, increasing the capacity of the ER to fold and degrade misfolded proteins, and inducing apoptosis if necessary. The UPR is controlled by three ER transmembrane proteins, IRE1, ATF6, and PERK, which initiate three intracellular signaling pathways that converge on the activation of a set of genes involved in restoring ER homeostasis. While the UPR is known to be essential for maintaining proteostasis in the ER, recent studies suggest that it interacts with other intracellular signaling pathways and metabolic pathways, affecting various cellular functions beyond proteostasis in the ER. Further study is needed to fully elucidate the role of the UPR.

What is the integrated stress response (ISR)?

The eukaryotic initiation factor 2 (eIF2) is a factor required for the initiation of protein synthesis from mRNA in the cell. The α-subunit of eIF2 is phosphorylated by four distinct eIF2α kinases (PERK, GCN2, PKR, HRI), which are activated by various stress conditions including ER stress、nutrient deprivation, viral infection and oxidative stress. Phosphorylation of eIF2α is an important regulatory mechanism so-called the integrated stress response (ISR). The ISR is thought to restore cellular homeostasis by decreasing global protein synthesis and selectively increasing the translation of specific stress-responsive genes. The phosphorylation of eIF2α, which inhibits the activity of eIF2B, a guanine nucleotide exchange factor required for recycling eIF2-GDP to eIF2-GTP, reducing the availability of active eIF2 required for translation and decreasing the overall rate of protein synthesis. This promotes the translation of specific mRNAs, such as those encoding ATF4 and CHOP, which play critical roles in stress adaptation and cell fate determination. The ISR has been reported to be involved in many diseases, including neurodegenerative disorders, cancer, inflammatory diseases, and cardiovascular diseases, and further research is expected in the future.